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Established in June 1942 as a B-17 Flying Fortress heavy bombardment squadron; it trained under the Second Air Force. The squadron deployed to the European Theater of Operations (ETO) in September 1942, being assigned to VIII Bomber Command in England. It began flying long-range strategic bombardment missions on 17 November 1942 and attacked such targets as submarine pens, docks, harbours, shipyards, motor works and marshalling yards in France, Germany and the Low Countries. It continued attacks on enemy cities, manufacturing centers, transportation links and other targets until the German capitulation in May 1945.

After combat missions ended, the squadron moved to St Trond Air Base in Belgium in July 1945, where it conducted photo-mapping and intelligence-gathering flights over Europe and North Africa which came under the name Project 'Casey Jones'. On 15 December 1945 it moved to Lechfeld airfield, Germany which it had bombed on 18 March 1944 and which it now used as an occupation base.

The 364th Bomb Squadron was inactivated in December 1946 in Germany.

During the Korean War, Tactical Air Command (TAC) trained aircrews at Langley AFB, Virginia. The three squadrons of the 4400th Combat Crew Training Group performing this mission were Air National Guard units that had been called up for the war. At the start of 1953, these squadrons were released to state control and the 423d Bombardment Squadron took over the mission, personnel, and equipment of the 115th Bombardment Squadron, which returned to the California guard.[1] It was then equipped with obsolete B-45 Tornado light bombers. The squadron was inactivated in 1954.

The squadron was reactivated in 1959 by Strategic Air Command (SAC) at MacDill AFB, Florida as a result of the phasing out of the B-47 Stratojet. Additional squadrons were activated as part of the consolation of Stratojet wings and the replacement of the B-47 by B-52 Stratofortresses. However, the squadron was never equipped or manned, but it was assigned administratively to several bases before being inactivated in 1961.